Downregulation of miR-146b-3p Inhibits Proliferation and Migration and Modulates the Expression and Location of Sodium/Iodide Symporter in Dedifferentiated Thyroid Cancer by Potentially Targeting MUC20

The dedifferentiation of differentiated thyroid cancer (DTC) is a challenging problem for radioactive iodine (131I) treatment, also known as radioiodine refractory differentiated thyroid cancer (RAIR-DTC). The purpose of this study was to further explore the mechanism of the redifferentiation of dedifferentiated thyroid cancer. Ineffective and effective groups of 131I therapy were analyzed and compared in both our clinical and TCGA samples. Whole-exome sequencing, mutation analysis, transcriptome analysis, and in vitro functional experiments were conducted. FLG, FRG1, MUC6, MUC20, and PRUNE2 were overlapping mutation genes between our clinical cases, and the TCGA cases only appeared in the ineffective group. The expression of miR-146b-3p target MUC20 was explored. The expression levels of miR-146b-3p and MUC20 were significantly increased, and the inhibition of miR-146b-3p expression significantly inhibited proliferation and migration, promoted apoptosis, regulated the expression and location of thyroid differentiation-related genes, and sodium/iodide symporter (NIS) in dedifferentiated thyroid cancer cells (WRO). Thus, miR-146b-3p potentially targets MUC20 participation in the formation of DTC dedifferentiation, resulting in resistance to 131I and the loss of the iodine uptake ability of DTC cancer foci, promoting refractory differentiated thyroid cancer. miR-146b-3p may be a potentially therapeutic target for the reapplication of 131I therapy in dedifferentiated thyroid cancer patients.

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Role of Radioactive Iodine for Adjuvant Therapy and Treatment of Metastases

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2007.0054 ◽

2007 ◽

Vol 5 (6) ◽

pp. 631-640 ◽

Cited By ~ 3

Author(s):

Jacqueline Jonklaas

Keyword(s):

Thyroid Cancer ◽

Side Effects ◽

Adjuvant Therapy ◽

Cancer Cells ◽

Differentiated Thyroid Cancer ◽

Sodium Iodide ◽

Radioactive Iodine ◽

Radioiodine Therapy ◽

Sodium Iodide Symporter ◽

Thyroid Cancer Cells

Normal thyrocytes and thyroid cancer cells are characterized by possession of a sodium iodide symporter. Radioiodine administration is a unique and powerful means of treating differentiated thyroid cancer because of the ability of thyroid cancer cells to concentrate beta-emitting radiolabeled iodine. Several manipulations, such as iodine depletion and thyroid hormone-stimulating hormone elevation, are used to enhance uptake of radiolabeled iodine by tumor cells. Adjuvant radioiodine therapy, given to patients without evidence of residual disease, enhances the sensitivity of subsequent surveillance and may decrease recurrence rates and mortality. However, its exact role in the management of low-risk patients merits further investigation. In contrast, radioactive iodine therapy used in patients with residual or metastatic disease clearly improves outcomes. Several studies show decreased recurrence and mortality rates in patients treated with radioiodine compared with those not receiving radioactive iodine. Adverse events from radioiodine therapy include salivary gland dysfunction, bone marrow suppression, and reproductive disturbances. Side effects of radioiodine therapy are generally greater when higher activities of radioiodine are used and may be transient or permanent. Secondary malignancies also may occur after radioiodine therapy. These side effects must be weighed against potential benefits, especially when radioactive iodine is used as adjuvant therapy. Stimulation of the expression of the sodium iodide symporter, or its introduction de novo into nonthyroid cells, is promising in treating poorly differentiated thyroid cancer and nonthyroid malignancies, respectively.

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Curcumin enhances the membrane trafficking of sodium iodide symporter and augments radioiodine uptake in dedifferentiated thyroid cancer cells via suppression of PI3K-AKT signaling pathway

Food & Function ◽

10.1039/d1fo01073e ◽

2021 ◽

Author(s):

Li Zhang ◽

Shichen Xu ◽

Xian Cheng ◽

Jing Wu ◽

Xiaowen Wang ◽

...

Keyword(s):

Thyroid Cancer ◽

Membrane Trafficking ◽

Differentiated Thyroid Cancer ◽

Sodium Iodide ◽

Radioactive Iodine ◽

Distant Metastases ◽

Sodium Iodide Symporter ◽

Akt Signaling Pathway ◽

Radioiodine Uptake ◽

Thyroid Cancer Cells

Radioactive iodine (RAI) is commonly used to treat differentiated thyroid cancer (DTC). A major challenge is dedifferentiation of DTC with the loss of radioiodine uptake. Patients with distant metastases have...

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Dual inhibition of BRAF and MEK increases expression of sodium iodide symporter in patient-derived papillary thyroid cancer cells in vitro

Surgery ◽

10.1016/j.surg.2019.04.076 ◽

2020 ◽

Vol 167 (1) ◽

pp. 56-63 ◽

Cited By ~ 2

Author(s):

Timothy M. Ullmann ◽

Heng Liang ◽

Maureen D. Moore ◽

Isra Al-Jamed ◽

Katherine D. Gray ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Papillary Thyroid Cancer ◽

Sodium Iodide ◽

Papillary Thyroid ◽

Sodium Iodide Symporter ◽

Dual Inhibition ◽

Thyroid Cancer Cells

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Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS

Theranostics ◽

10.7150/thno.57689 ◽

2021 ◽

Vol 11 (13) ◽

pp. 6251-6277

Author(s):

Ji Min Oh ◽

Byeong-Cheol Ahn

Keyword(s):

Thyroid Cancer ◽

Signaling Pathway ◽

Differentiated Thyroid Cancer ◽

Sodium Iodide ◽

Molecular Mechanisms ◽

Radioactive Iodine ◽

Intracellular Localization ◽

Sodium Iodide Symporter ◽

Pathway Activity

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Taking Advantage of the TGFB1 Biology in Differentiated Thyroid Cancer to Stimulate Sodium Iodide Symporter (NIS)-Mediated Iodide Uptake in Engineered Mesenchymal Stem Cells

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.2114 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A1033-A1033

Author(s):

Yang Han ◽

Viktoria F Koehler ◽

Nathalie Schwenk ◽

Kathrin A Schmohl ◽

Rebekka Spellerberg ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Nis Gene

Abstract The sodium iodide symporter (NIS) mediates the active transport of iodide into thyroid follicular cells, providing the basis for the use of radioiodide for diagnostic imaging and therapy of differentiated thyroid cancer and also non-thyroidal tumors after tumor-selective NIS gene transfer. Based on their excellent tumor-homing capacity, mesenchymal stem cells (MSCs) can be employed as tumor-selective NIS gene delivery vehicles. Transgenic expression of NIS in genetically engineered MSCs allows noninvasive imaging of functional NIS expression as well as therapeutic application of 131I. The use of promoters activated by tumor micromilieu-derived signals to drive NIS expression enhances selectivity and effectiveness, while limiting potential off-target effects. In this study we aimed to exploit the central role of transforming growth factor B1 (TGFB1) in tumor milieu-associated signaling using a TGFB1-inducible synthetic SMAD-responsive promoter to selectively drive NIS-transgene expression in engineered MSCs (SMAD-NIS-MSC) in the context of differentiated thyroid cancer based on the critical role of TGFB1 in the pathogenesis of radioiodine refractory differentiated thyroid cancer. To evaluate the TGFB1 expression in thyroid cancer cell lines, the TGFB1 concentration in conditioned medium (CM) from an array of established human papillary thyroid cancer (PTC) cell lines (BCPAP and K1) was measured by ELISA. BCPAP-CM showed a higher concentration of TGFB1, while a lower concentration was measured in K1-CM. Stimulation of SMAD-NIS-MSCs with PTC-CM showed a significant increase of NIS-mediated radioiodide-125 uptake in these MSCs in vitro. In addition, iodide uptake in SMAD-NIS-MSCs was significantly stimulated by co-culture with thyroid cancer cells. Cell migration assay was performed to validate the effect of PTC-CM in MSC recruitment. MSCs subjected to a gradient between tumor CM and serum free medium showed a directed chemotaxis towards CM with increased forward migration index (FMI) and center of mass (CoM). In a next step, based on the in vitro studies, SMAD-NIS-MSCs will be systemically applied via the tail vein to mice harboring subcutaneous PTC tumors and tumoral iodide uptake will be monitored by 123I-scintigraphy. Taken together, these data indicate the feasibility of commandeering TGF-β/SMAD signaling in the TGFB1-rich tumor environments of radioiodine refractory differentiated thyroid carcinomas to re-establish functional NIS expression using engineered mesenchymal stem cells as therapy vehicles.

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Targeting BRAFV600E using nanoliposomal-small interfering RNA restores the expression of sodium iodide symporter and increases the uptake of iodide in thyroid cancer cells

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2011.06.349 ◽

2011 ◽

Vol 213 (3) ◽

pp. S143

Author(s):

Daniel Buitrago ◽

Hasan Aldailami ◽

Alexander Veach ◽

Filippo Filicori ◽

Xavier M. Keutgen ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Small Interfering Rna ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Interfering Rna ◽

Thyroid Cancer Cells

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Reverting iodine avidity of radioactive-iodine refractory thyroid cancer with a new tyrosine kinase inhibitor (K905-0266) excavated by high-throughput NIS (sodium iodide symporter) enhancer screening platform using dual reporter gene system

Oncotarget ◽

10.18632/oncotarget.24159 ◽

2018 ◽

Vol 9 (6) ◽

pp. 7075-7087 ◽

Cited By ~ 7

Author(s):

Ji Min Oh ◽

Senthilkumar Kalimuthu ◽

Prakash Gangadaran ◽

Se Hwan Baek ◽

Liya Zhu ◽

...

Keyword(s):

Thyroid Cancer ◽

Tyrosine Kinase Inhibitor ◽

High Throughput ◽

Sodium Iodide ◽

Radioactive Iodine ◽

Kinase Inhibitor ◽

Sodium Iodide Symporter ◽

Dual Reporter ◽

Reporter Gene System ◽

Screening Platform

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Mediator complex subunit 16 is down-regulated in papillary thyroid cancer, leading to increased transforming growth factor-β signaling and radioiodine resistance

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.012404 ◽

2020 ◽

Vol 295 (31) ◽

pp. 10726-10740

Author(s):

Hongwei Gao ◽

Peirong Bai ◽

Lin Xiao ◽

Mengjia Shen ◽

Qiuxiao Yu ◽

...

Keyword(s):

Cell Migration ◽

Thyroid Cancer ◽

Growth Factor ◽

Sodium Iodide ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Mediator Complex ◽

Papillary Thyroid ◽

Sodium Iodide Symporter

Mediator complex subunit 16 (MED16) is a component of the mediator complex and functions as a coactivator in transcriptional events at almost all RNA polymerase II–dependent genes. In this study, we report that the expression of MED16 is markedly decreased in papillary thyroid cancer (PTC) tumors compared with normal thyroid tissues. In vitro, MED16 overexpression in PTC cells significantly inhibited cell migration, enhanced sodium/iodide symporter expression and iodine uptake, and decreased resistance to radioactive 131I (RAI). Conversely, PTC cells in which MED16 had been further knocked down (MED16KD) exhibited enhanced cell migration, epithelial–mesenchymal transition, and RAI resistance, accompanied by decreased sodium/iodide symporter levels. Moreover, cell signaling through transforming growth factor β (TGF-β) was highly activated after the MED16 knockdown. Similar results were obtained in MED12KD PTC cells, and a co-immunoprecipitation experiment verified interactions between MED16 and MED12 and between MED16 and TGF-βR2. Of note, the application of LY2157299, a potent inhibitor of TGF-β signaling, significantly attenuated MED16KD-induced RAI resistance both in vitro and in vivo. In conclusion, our findings indicate that MED16 reduction in PTC contributes to tumor progression and RAI resistance via the activation of the TGF-β pathway.

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